Radiation therapy following breast conservation surgery: can it ever be avoided?
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Breast Neoplasms↗
Biomedical subjects
M Levine
Publications and source records attributed to M Levine.
Pharmacokinetic model of ascorbic acid in healthy male volunteers during depletion and repletion.
PURPOSE: To develop a new pharmacokinetic model for ascorbic acid (vitamin C) since no previously published model describes ascorbic acid absorption and disposition over a broad physiologic range of doses and plasma concentrations. METHODS: A new model was developed through exploratory simulations. The model was fitted to pharmacokinetic data obtained from seven healthy volunteers who underwent ascorbic acid depletion then gradual repletion. Concentrations of ascorbic acid were measured in plasma and urine. Final pharmacokinetic model parameter estimates were obtained using nonlinear regression analysis. RESULTS: The new model included saturable absorption, distribution and renal tubular reabsorption parameters. The model described ascorbic acid concentrations in plasma, cells, and urine during depletion and gradual repletion phases with a residual error less than 15%. CONCLUSIONS: The model was useful for obtaining a new understanding of the likely causes for the complex concentration-time profile observed during gradual repletion. At doses of 200 to 2500 mg per day, the plateau in pre-dose concentrations is largely due to apparent saturation of tissue uptake and less a function of oral bioavailability and renal excretion than previously thought.
Adult↗
Effects of legally mandated child-abuse reports on the therapeutic relationship: a survey of psychotherapists.
In a national survey of 907 licensed psychologists regarding mandated reporting of child maltreatment, predictors of outcome included: therapeutic alliance; role strain; therapist explicitness; family vs. individual treatment; and whether or not the client was the perpetrator. Therapists were asked to describe a case involving reporting, its impact on treatment, informed consent procedures, as well as their own attitudes and beliefs. Implications for research are discussed, and recommendations for clinical training and practice are offered.
Adult↗
Pulmonary toxicity of high-dose chemotherapy for breast cancer: a non-invasive approach to diagnosis and treatment.
Drug-induced pulmonary toxicity is one of the most frequent non-hematologic toxicities in breast cancer patients receiving high-dose chemotherapy with cyclophosphamide, cisplatin and BCNU (CY/CDDP/BCNU). A non-invasive clinical scoring system was utilized in an attempt to diagnose and treat early lung toxicity in 64 consecutive breast cancer patients undergoing CY/CDDP/BCNU supported by peripheral blood progenitor cells. Following hospital discharge, patients who developed symptoms suggestive of lung toxicity were evaluated with physical examination, DLCO, 2-min walking oximetry and a chest radiograph. Clinically weighted scores were assigned as follows: crackles on lung exam, 2; decrease in corrected DLCO by > 10% from baseline, 3; decrease in O2 saturation by > or = 4% with a 2-min walk, 3; and interstitial infiltrates on chest radiograph, 3. Patients with scores > or = 6 were treated with prednisone (60 mg p.o. twice a day followed by a 2-month taper). Treatment was instituted in 37 patients (58%) a median of 56 days after high-dose chemotherapy. Steroid therapy was associated with rapid clinical improvement in most patients. No fatal complications or chronic pulmonary fibrosis was seen. This non-invasive clinical scoring system can be utilized as a model for the early diagnosis of lung toxicity. Further investigation is warranted for the development of preventative measures against this syndrome.
Adult↗
Anaesthesia for insertion of ear tubes in children: comparison of propofol, thiopentone and halothane.
To determine the quality of anaesthesia and speed of recovery after propofol anaesthesia for myringotomy in children, 100 children 2-12 years were randomized to one of four anaesthetic regimens for induction/maintenance: thiopentone (STP) (5 mg.kg-1)/halothane, propofol (3 mg.kg-1)/halothane, halothane/halothane or propofol (3 mg.kg-1)/propofol bolus (0.5 mg.kg-1 every 3 min (10 mg.kg-1.h-1)). Nitrous oxide (70%) in oxygen (30%) was used to facilitate insertion of an intravenous catheter and was continued throughout the anaesthetic. We found that the incidence of intraoperative movement in response to surgical stimulation was significantly greater in the prop/prop group 32%, compared with the three other groups (P < 0.02). Although some recovery variables (time to response to questions, sit unaided, tolerate oral fluids, and discharge with fluids) were achieved more rapidly by the prop/ prop group than the other three groups, the times to open eyes, obey commands and, most importantly, discharge from recovery without fluids did not differ between the prop/prop and the hal/ hal groups. We conclude that there is little benefit in using propofol as an induction agent alone or in combination with a propofol maintenance anaesthetic for paediatric myringotomy and tube surgery.
Anesthesia Recovery Period↗
Use of a new vitamin C-deficient diet in a depletion/repletion clinical trial.
To conduct an inpatient study on the recommended dietary allowance (RDA) for vitamin C, we developed a unique vitamin C-deficient diet using a nutrient database and selective menus. Fourteen different menus were developed offering > 300 items with 0-2.4 mg vitamin C per serving. During the 4-6 mo volunteers were hospitalized, daily dietary vitamin C was restricted to < or = 5.0 mg. The mean daily dietary vitamin C intake was < 3.9 mg for the seven study subjects. With concurrent supplementation, the diet provided > or = 85% of the RDA for 17 essential nutrients. Within 3 wk of admission the diet induced vitamin C deficiency as indicated by plasma concentrations, which decreased from 23 +/- 6.9 to 6.9 +/- 2.0 mumol/L. Daily intake of vitamin C and five other nutrients was determined by nutrient database analyses. Mean energy, protein, the iron were 105-185% of the RDA and total and saturated fat were 32% and 10% of energy, respectively. Weight and nutritionally relevant indexes remained normal. Dietary adherence, calculated by the number of days with < or = 5.0 mg vitamin C per total study days, was 88-98% per repletion dose. Computer analyses of menu selections permitted individual preferences to be met while restricting vitamin C intake to < or = 5.0 mg/d. There were no complications from the diet during the depletion and repletion phase. With this diet, ascorbic acid pharmacokinetics for escalating doses could be determined in healthy volunteers.
Ascorbic Acid↗
Treatment of thrombotic disorders in cancer patients.
Cancer patients are in a hypercoagulable state. The pathogenesis of thrombosis in malignancy is multifactorial with mechanisms including release of procoagulants by tumour cells, comorbid predisposing factors (bed rest, infection, surgery, etc.) and anti-cancer drugs. Cancer patients with established venous thromboembolism are more likely to develop recurrent venous thromboembolism during treatment with oral anticoagulants. This paper reviews the use of heparin for the treatment of thrombotic disorders in cancer patients. Treatment of acute venous thrombosis comprises initial heparin administration, which for a cancer patient should last for at least 5 days, followed by administration of oral anticoagulants. Low-molecular-weight heparins (LMWHs) have been shown to be as safe and effective as standard heparin for the treatment of acute deep vein thrombosis. Recent meta-analyses have revealed lower mortality rates with LMWH than with standard heparin, indicating that LMWH may exert an inhibitory effect on tumour growth that is not observed with standard heparin.
Heparin↗
Dorsoventral patterning of the vertebrate neural tube is conserved in a protochordate.
The notochord and dorsal ectoderm induce dorsoventral compartmentalization of the vertebrate neural tube through the differential regulation of genes such as HNF-3beta, Pax3, Pax6 and snail. Here we analyze the expression of HNF-3beta and snail homologues in the ascidian, Ciona intestinalis, a member of the subphylum Urochordata, the earliest branch in the chordate phylum. A combination of in situ hybridization and promoter fusion analyses was used to demonstrate that the Ciona HNF-3beta homologue is expressed in the ventralmost ependymal cells of the neural tube, while the Ciona snail homologue is expressed at the junction between the invaginating neuroepithelium and dorsal ectoderm, similar to the patterns seen in vertebrates. These findings provide evidence that dorsoventral compartmentalization of the chordate neural tube is not an innovation of the vertebrates. We propose that precursors of the floor plate and neural crest were present in a common ancestor of both vertebrates and ascidians.
Amino Acid Sequence↗
Regulation of a dpp target gene in the Drosophila embryo.
In Drosophila, two TGF-beta growth factors, dpp and screw, function synergistically to subdivide the dorsal ectoderm into two embryonic tissues, the amnioserosa and dorsal epidermis. Previous studies have shown that peak dpp activity is required for the localized expression of zerknüllt (zen), which encodes a homeodomain transcription factor. We present evidence that zen directly activates the amnioserosa-specific expression of a downstream target gene, Race (Related to angiotensin converting enzyme). A 533 bp enhancer from the Race promoter region is shown to mediate selective expression in the amnioserosa, as well as the anterior and posterior midgut rudiments. This enhancer contains three zen protein binding sites, and mutations in these sites virtually abolish the expression of an otherwise normal Race-lacZ fusion gene in the amnioserosa, but not in the gut. Genetic epistasis experiments suggest that zen is not the sole activator of Race, although a hyperactivated form of zen (a zen-VP16 fusion protein) can partially complement reduced levels of dpp activity. These results suggest that dpp regulates multiple transcription factors, which function synergistically to specify the amnioserosa.
Animals↗
Characterization of a notochord-specific enhancer from the Brachyury promoter region of the ascidian, Ciona intestinalis.
We present evidence that the embryo of the ascidian, Ciona intestinalis, is an easily manipulated system for investigating the establishment of basic chordate tissues and organs. Ciona has a small genome, and simple, well-defined embyronic lineages. Here, we examine the regulatory mechanisms underlying the differentiation of the notochord. Particular efforts center on the regulation of a notochord-specific Ciona Brachyury gene (Ci-Bra). An electroporation method was devised for the efficient incorporation of transgenic DNA into Ciona embryos. This method permitted the identification of a minimal, 434 bp enhancer from the Ci-Bra promoter region that mediates the notochord-restricted expression of both GFP and lacZ reporter genes. This enhancer contains a negative control region that excludes Ci-Bra expression from inappropriate embryonic lineages, including the trunk mesenchyme and tail muscles. Evidence is presented that the enhancer is activated by a regulatory element which is closely related to the recognition sequence of the Suppressor of Hairless transcription factor, thereby raising the possibility that the Notch signaling pathway plays a role in notochord differentiation. We discuss the implications of this analysis with regard to the evolutionary conservation of integrative enhancers, and the subdivision of the axial and paraxial mesoderm in vertebrates.
Amino Acid Sequence↗
Recruiting women for breast screening. Family Physician Model strategy.
OBJECTIVE: To determine whether family physicians would participate in the Family Physician Model (FPM) recruitment strategy for mammography screening, whether participating physicians differed from non-participating physicians, and whether the strategy would recruit 70% of eligible women in the participating practices. DESIGN: Family physicians were invited to participate in the project. Staff from the Ontario Breast Screening Program-Hamilton Centre (OBSP-H) identified eligible women, prepared personalized letters recommending screening, and monitored compliance. Participating and non-participating physicians were asked to complete a questionnaire. SETTING: Family practices in Dundas, Ancaster, and Hamilton, Ont. PARTICIPANTS: Women aged 50 years and older who met eligibility criteria for screening. Family physicians in Dundas, Ancaster, and Hamilton. INTERVENTION: Family physicians were approached by the Health Promotion Officer at the OBSP-H about participating in the FPM. Eligible women in their practices were sent letters recommending breast screening. MAIN OUTCOME MEASURES: Percentage of family physicians agreeing to participate in the FPM, characteristics of participating and non-participating physicians, and percentage of eligible women who scheduled mammograms. RESULTS: Of the 114 family physicians approached, 76 (67%) agreed to participate. Significantly more participating than non-participating physicians were in group practice and had certification in family medicine. In response to the letters, 54% of eligible women obtained mammograms. Because 12% of women were ineligible since they had been referred for screening within the previous 12 months, 66% of women in the participating practices actually obtained mammograms over the 2-year period-almost the target 70%. CONCLUSION: The FPM is a successful recruitment strategy.
Aged↗
The regulation of enhancer-promoter interactions in the Drosophila embryo.
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Animals↗
The Fab-7 element of the bithorax complex attenuates enhancer-promoter interactions in the Drosophila embryo.
Enhancers integrate positive and negative regulatory information to direct localized patterns of gene expression in the Drosophila embryo. Here we present evidence for the occurrence of cis regulatory elements that control the levels of gene expression by modulating enhancer-promoter interactions. For this purpose we have investigated the Drosophila bithorax complex (BX-C) because genetic studies suggest that the BX-C contains as much as 300 kb of cis regulatory information. A specialized DNA element, Fab-7, has been proposed to function as a boundary element that separates the iab-6 and iab-7 cis regulatory regions within the Abd-B domain of the BX-C. A 1.2-kb Fab-7 DNA fragment was placed between divergently transcribed white and lacZ test promoters and challenged with several defined enhancers expressed in the early embryo. These studies suggest that Fab-7 functions as an attenuator, which weakens gene expression by reducing enhancer-promoter interactions. Fab-7 selectively blocks distal enhancers in an orientation-independent fashion, and can function when located far from either the distal enhancer or target promoter. Fab-7 may be related to insulator DNAs, which flank genetic loci and functionally isolate neighboring genes. We propose that specialized DNA elements, such as the Fab-7 attenuator, might play a general role in controlling the levels of gene expression by modulating enhancer-promoter interactions.
Animals↗
Randomized clinical trial of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer: an update. Ontario Clinical Oncology Group.
BACKGROUND: Breast-conservation surgery is now commonly used to treat breast cancer. Postoperative breast irradiation reduces cancer recurrence in the breast. There is still controversy concerning the necessity of irradiation of the breast in all patients. PURPOSE: We present an update of results from a randomized clinical trial designed to examine the efficacy of breast irradiation following conservation surgery in the treatment of women with axillary lymph node-negative breast cancer. The patients were enrolled from April 1984 through February 1989. Initial results were published in 1992 after a median follow-up time of 43 months. It was reported that recurrence of cancer in the breast occurred in 5.5% of the patients who received breast irradiation compared with 25.7% of those who did not. No difference in survival was detected between the two treatment groups. Now that the median patient follow-up has reached 7.6 years, the trial end points have been re-examined and an attempt has again been made to identify a group of patients at low risk for recurrence of cancer in the breast. METHODS: Eight hundred thirty-seven patients with node-negative breast cancer were randomly assigned to receive either radiation therapy (n = 416) or no radiation therapy (n = 421) following lumpectomy and axillary lymph node dissection. The cumulative local recurrence rate as a first event, distant recurrence (i.e., occurrence of metastasis) rate, and overall mortality rate for the treatment groups were described by the Kaplan-Meier method and compared with the use of the logrank test. The Cox proportional hazards model was used to adjust the observed treatment effect for the influence of various prognostic factors (patient age, tumor size, estrogen receptor level, and tumor histology) at study entry on the outcomes of local breast recurrence, distant recurrence, and overall mortality. All P values resulted from the use of two-tailed statistical tests. RESULTS: One hundred forty eight (35%) of the nonirradiated patients and 47 (11%) of the irradiated patients developed recurrent cancer in the breast (relative risk for patients in the former versus the latter group = 4.0; 95% confidence interval = 2.83-5.65; P < .0001). Ninety-nine (24%) of the patients in the former group have died compared with 87 (21%) in the latter group. Age (< 50 years), tumor size (> 2 cm), and tumor nuclear grade (poor) continued to be important predictors for local breast relapse. On the basis of these factors, we were unable to identify a subgroup of patients with a very low risk for local breast cancer recurrence. Tumor nuclear grade, as previously reported, and tumor size were important predictors for mortality. CONCLUSIONS: Breast irradiation was shown to reduce cancer recurrence in the breast, but there was no statistically significant reduction in mortality. A subgroup of patients with a very low risk for local breast recurrence who might not require radiation therapy was not identified.
Adult↗
A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis.
BACKGROUND: Cerebral metastasis is a common oncologic problem that occurs in 15-30% of cancer patients; approximately half such metastases are single. Previous retrospective studies and two randomized trials reported that the addition of surgical extirpation prior to radiation therapy increased survival, neurologic function, and quality of life compared with radiation alone in patients with a single brain metastasis. METHODS: A randomized controlled trial was conducted in which patients with a single brain metastasis were allocated to undergo radiation alone or surgery plus radiation. Radiation consisted of 3000 centigray to the whole brain in 10 fractions. RESULTS: Forty-three patients received radiation alone and 41 patients surgery plus radiation. All but two of the study patients died. No difference in survival was detected between the groups; the median survival for the radiation group was 6.3 months (95% confidence interval, 3-11.4) compared with 5.6 months for the surgery plus radiation group (95% confidence interval, 3.9-7.2) (P = 0.24). Most patients died within the first year (69.8% in the radiation arm vs. 87.8% in the surgery plus radiation arm). There were no significant differences in the 30-day mortality, morbidity, or causes of death. Extracranial metastases was an important predictor of mortality (relative risk, 2.3). The mean proportion of days that the Karnofsky performance status was > or = 70% did not differ between the 2 groups. CONCLUSIONS: This trial failed to demonstrate that the addition of surgery to radiation therapy improved outcome of patients with a single brain metastasis. Thus, the efficacy of surgery plus radiation compared with radiation alone needs to be addressed by further clinical trials and/or a meta-analysis.
Brain Neoplasms↗
Long-range repression in the Drosophila embryo.
Transcriptional repressors can be characterized by their range of action on promoters and enhancers. Short-range repressors interact over distances of 50-150 bp to inhibit, or quench, either upstream activators or the basal transcription complex. In contrast, long-range repressors act over several kilobases to silence basal promoters. We describe recent progress in characterizing the functional properties of one such long-range element in the Drosophila embryo and discuss the contrasting types of gene regulation that are made possible by short- and long-range repressors.
Animals↗
The gap protein knirps mediates both quenching and direct repression in the Drosophila embryo.
Transcriptional repression is essential for establishing localized patterns of gene expression during Drosophila embryogenesis. Several mechanisms of repression have been proposed, including competition, quenching and direct repression of the transcription complex. Previous studies suggest that the knirps orphan receptor (kni) may repress transcription via competition, and exclude the binding of the bicoid (bcd) activator to an overlapping site in a target promoter. Here we present evidence that kni can quench, or locally inhibit, upstream activators within a heterologous enhancer in transgenic embryos. The range of kni repression is approximately 50-100 bp, so that neighboring enhancers in a modular promoter are free to interact with the transcription complex (enhancer autonomy). However, kni can also repress the transcription complex when bound in promoter-proximal regions. In this position, kni functions as a dominant repressor and blocks multiple enhancers in a modular promoter. Our studies suggest that short-range repression represents a flexible form of gene regulation, exhibiting enhancer- or promoter-specific effects depending on the location of repressor binding sites.
Amino Acid Sequence↗
Regulation of two pair-rule stripes by a single enhancer in the Drosophila embryo.
Previous studies on the regulation of the segmentation gene even-skipped (eve) have centered on the transcription of stripe 2. Here, we characterize another enhancer module contained within the complex eve promoter that directs expression of stripes 3 and 7. This enhancer is approximately 500 bp in length and maps approximately 3.3 kb upstream of the transcription start site. The stripe 3 + 7 enhancer appears to be regulated by one or more ubiquitously distributed activators, including components of a JAK-Stat pathway. The two-stripe pattern results via multiple tiers of repressors which delimit this ubiquitous activation. The zinc finger repressor hunchback appears to be responsible for establishing the anterior border of stripe 3 and the posterior border of stripe 7. knirps, a member of the nuclear receptor family of transcription factors, appears to establish the posterior border of stripe 3 and the anterior border of stripe 7. Activator and repressor proteins bind in vitro to several sites within the enhancer. These findings suggest a general model for the regulation of segmentation stripes, whereby enhancers integrate positional information provided by broadly distributed activators and spatially restricted repressors.
Alleles↗